December 2011 e-journal club

From our
facility to yours--wishing you Happy Holidays and a New Year free of
aspiration, C.Diff and high gastric residuals!

Greetings,

We do not host training programs in December, but here at UVA there
is never a danger that we will become too idle. In between
stress-testing our gastric emptying at Thanksgiving and preparing for
the next round of holiday festivities, we made time for journal club.
We have been awaiting the full results of this month’s article,
and moved it into the fast-track for journal club once it was
available.

This study was part of the very large National Heart, Lung, and
Blood Institute (NHLBI) ARDS Clinical Trial Network study – the
EDEN-OMEGA trial. EDEN-OMEGA was a multi-center study that was
designed to answer 2 questions by randomizing patients with acute lung
injury (ALI)/ARDS to receive omega-3/gamma-linolenic fatty acids with
antioxidants vs placebo and also trophic compared to full
feeding in a 2X2 factorial design. In the OMEGA arm of the study,
participants were randomized to receive a twice daily supplement of
Omega-3 and gamma-linolenic fatty acids with vitamin C and E,
b-carotene, zinc, selenium, L-carnitine and taurine in doses similar to
1600-1800 calories of the commercial formula designed for ALI/ARDS
patients. The placebo supplement was isocaloric composed of
carbohydrates and 16 gms more protein/day than the study
supplement.

The primary outcome of this study was ventilator-free days (number
of days alive and breathing without assistance from randomization until
day 28). Secondary end points included 60-day mortality before
hospital discharge with unassisted breathing, number of ICU- and organ
failure–free days, frequency of gastrointestinal intolerance, plasma
levels of IL-6 and IL-8 on days 3 and 6, urinary levels of series 4 and
5 leukotrienes on day 6, and development of new infections.
Selected plasma fatty acid levels were also measured at baseline and on
days 3, 6, and 12.

There were more than 30 exclusion criteria (too many to list in
full), but the most common reasons patients were excluded were previous
severe chronic lung disease, greater than 48 hrs since ALI diagnosis or
72 hours since intubation, inability to obtain consent, likely fatal
underlying disease, recent intracranial hemorrhage, severe liver
disease, moribund, refractory shock, coagulopathy or refused
consent

Major Results reported by authors:

This study was planned to have a maximum enrollment of 1000
patients, but the data and safety monitoring board stopped the study at
the first interim analysis after examining data from 272 patients.

The n-3 supplement group had significantly fewer ventilator-free
days to study day 28 compared with controls (14.0 vs 17.2, P=0.02) and
significantly fewer ICU-free days (14.0 vs 16.7, P=0.04).

The n-3 supplement group also appeared to have greater 60-day
mortality than the placebo group, with 38 of the 143 patients (26.6%)
expired compared with 21 of the 129 (16.3%) in the control group
(P=0.054). After the investigators adjusted for baseline
variables that are associated with mortality in ALI, the 60-day
mortality in n-3 group was 25.1% vs 17.6% in the control group
(P=0.11).

Patients in both groups received an average of 85% of the planned
twice-daily dosages of the study supplement. Patients receiving the n-3
supplement had significantly more instances of diarrhea, which occurred
in 28.7% of the n-3 group and 20.9% of the control group (P=0.001).

Plasma EPA levels were increased 8-fold on days 3, 6, and 12 in the
study group, but were unchanged in the control group. Plasma levels of
the arachidonic acid, IL-6, IL-8, leukotriene E4, leukotriene E5 and
urinary levels of F2-isoprostane were not significantly different
between the study and control groups. Urinary levels of
F3-isoprostanes (derived from n-3 fatty acids) were significantly
higher in the n-3 group on day 6 compared with controls.

Author’s Conclusions:

The authors concluded that: “..twice-daily enteral supplementation
of n-3 fatty acids, GLA, and antioxidants change plasma levels of n-3
fatty acids, but do not improve clinical outcomes or biomarkers of
systemic inflammation in patients with ALI and in fact may be
harmful.”

Evaluation:

This was a double-blind, randomized study that has the advantage
over previous studies of EPA/GLA/antioxidants of being multi-centered,
and importantly, does not use a high-fat control formula. The use
of a supplement separate from enteral feedings allowed patients to
receive the study formula without the delays that can arise from
enteral feeding interruptions or intolerance.

The fact that the results of this study suggest that
EPA/GLA/antioxidants may be harmful in ALI/ARDS was a surprise and has
led to a number of theories about why the results may be so different
from the previous studies. The most obvious thought would be that
perhaps EPA/GLA/antioxidants only appear to have benefits when compared
to potentially detrimental high-fat enteral feedings during
ALI/ARDS. Of course, it is conceivable that continuous infusion
of EPA/GLA/antioxidants in concert with providing the full spectrum of
nutrients in enteral feedings has different physiologic effects than
2X/day bolus feedings. There is data that continuous enteral
feeding with omega-3 fatty acids will affect the composition of cell
membrane phospholipids within 7 days1, but it is unclear if
a 2X/day bolus delivery would affect the composition of cell membranes
quite so rapidly.

The other aspect of this study that is important to remember is that
the patients in the OMEGA study were part of a larger trial with a 4X4
factorial design, meaning that approximately ½ of the patients in both
groups would have been receiving only trophic feedings for the first
6-7 days of the study. The control patients did receive 16 gm
more protein/day than the study supplement group – a difference that
would not be expected to impact outcomes in fully fed patients.
However, in those patients receiving minimal nutrition for
6+ days, the increased carbohydrate and protein provided to
the control group of the OMEGA arm could theoretically have
crossed a threshold and been enough extra nutrition to impact
outcome. It is also unclear if receiving minimal nutrition during
critical illness and using the additional EPA/GLA to meet energy needs
could have altered the effects of the supplement.

Another possible explanation is that EPA/GLA/antioxidants simply may
not offer any clinical advantage in ALI/ARDS when “modern”
lung-protective ventilation, early antibiotic, adequate resuscitation,
adequate glucose control, etc. strategies are used. It is also
possible that the positive effects seen in previous studies were simply
because those studies are far too small to reliably study outcome in a
diverse population of critically ill patients. Even though the
OMEGA study was stopped early, it was still nearly 3 times larger than
the 2006 study of EPA/GLA/antioxidants (272 compared to 103 patients
analyzed).2 In populations of critically ill adults,
it required an “n” of 1696 total patients to be able to firmly
establish that a therapy in septic patients did not have benefits,
after an earlier study with smaller numbers of the sickest patients
actually suggested a benefit in that subgroup (Xigris®
study).3 There is no other facet of critical care in
which it would be acceptable to make changes in clinical practice based
on studies of only 103 patients, or even a meta analysis of 411
patients.4

Our Take Home Message

Twice-daily enteral supplementation of n-3 fatty acids, GLA, and
antioxidants does not improve clinical outcomes in patients with ALI,
and in fact, may be harmful.

There
is a need for (much) larger multicenter trials of enteral formulas
containing EPA/GLA/antioxidants compared to standard feedings
before these formulas are routinely used in clinical
practice

The
nutrition support and medical community has learned too many times over
the potential negative effects of using therapies before they are
adequately tested – to repeat those mistakes, knowing what we do today,
would be foolish in the extreme.